1. Field of the Invention
This invention relates generally to radiopharmaceutical agents and more particularly concerns chelates of radiolabelled metals and N-(tri-substituted alkyl)-iminodiacetic acids or salts thereof which function as radiopharmaceutical liver imaging and function agents.
2. Description of the Prior Art
The rate of disappearance of an intravenously administered radiopharmaceutical agent from the plasma is related to both its distribution throughout the body and its elimination from the body. An analysis of the clearance, or rate of disappearance, of the radiopharmaceutical agent from the plasma--which can be represented by a plot of the logarithm of the experimentally measured radiopharmaceutical activity in the plasma as the ordinate versus time after administration as the abscissa--can define the number and sizes of the individual compartments of distribution of the radiopharmaceutical agent within the body. Since the clearance of the radiopharmaceutical agent from each compartment to the next is an exponential function, the individual components of the experimentally measured plasma clearance curve can be identified by a process of curve peeling. The process of curve peeling or stripping can be performed manually or by means of a computer using standard pharmaceutical computer programs such as CSTRIP and NONLIN. A. J. Stedman and J. G. Wagner, Journal of Pharmaceutical Sciences, Vol. 65, No. 7, July 1976, pp. 1006-1010; C. M. Metzler, G. L. Elfing and A. J. McEwen, Biometrics, Vol. 30, No. 3, September 1974.
The terminal slope of the clearance curve represents the liver component after equilibration in all the compartments, if the liver is the only ultimate exit from the first compartment (plasma being part of the first volume). By the process of curve stripping, the other exponential functions can be identified. This is done by manually extrapolating the terminal linear portion back to the ordinate and subtracting this extrapolated line from the original curve to obtain a new set of points. A new curve or straight line most closely approximating these new points is thereby identified, again having a terminal linear portion that defines another slope corresponding to a second compartment of distribution. This process of curve stripping is continued until arriving at a final exponential function, that is, until the points obtained as the difference between a curve and its extrapolated terminal linear portion are most closely approximated by a straight line. The number of exponential functions defines the number of individual compartments or volumes of distribution, and their sum defines the total plasma clearance curve. In the alternative this operation can be performed using a computer with available computer programs.
A two-compartment model predicts that a plot of the logarithm of radiopharmaceutical activity in either compartment (in the case of liver function, (1) in the plasma or whole blood or (2) in the hepatobiliary system) versus time after administration is represented by the sum of two exponential functions. Fitting the sums of the exponential functions to plots of the logarithm of observed radiopharmaceutical activity in a compartment versus time permits the determination of transfer constants and compartmental values. Deviation of such constants and values, and hence of the measured clearance curves, from corresponding constants, values and clearance curves, respectively, for a normally functioning liver permits diagnosis of liver ailments. If such a semi-quantitative analysis of the clearance through the liver can be made, the radiopharmaceutical agent can be used not only to externally image the liver put also to assess liver function.
The conventional radiopharmaceutical agent for external imaging of the liver and assessment of liver function is a complex of rose bengal withe the radionuclide iodine-131. The .sup.131 I-rose bengal complex is particularly well suited for this purpose because it is excreted through the liver exclusively, not through the kidneys or through both the liver and the kidneys. Due to its exceptionally high liver specificity, .sup.131 I-rose bengal appears to follow the two-compartment model for organ function assessment radiopharmaceutical agents. After intravenous injection, .sup.131 I-rose bengal is cleared from the blood, localized in the hepatocytes and excreted into the bile enroute to the bowel. The clearance from the blood is by active transport across the polygonal cell membranes, followed by excretion first into the biliary passages and ultimately into the gastrointestinal tract. There is no significant reabsorption of .sup.131 I-rose bengal from the gastrointestinal tract in normal subjects.
However, .sup.131 I-rose bengal suffers the disadvantage of containing the iodine-131 radionuclide which emits gamma rays having the relatively high energy of 0.364 MeV, thereby imposing a relatively low limit on the maximum permissible administration dosage of .sup.131 I-rose bengal. Further the 8 day half life of the iodine-131 radionuclide results in an excessive residual radiation dose following administration of millicurie quantities of .sup.131 I-rose bengal and performance of the test. This residual radiation is a disadvantage per se and also necessitates that successive radiopharmaceutical tests be spaced by a sufficient number of days after administration of .sup.131 I-rose bengal to permit the background radiation to decay to a sufficiently low level. In addition, in cases of decreased hepatic uptake due to disease, the long half life of iodine-131 creates a problem of measuring the radioactivity level of .sup.131 I-rose bengal itself in the liver against a high radiation background of .sup.131 I-rose bengal remaining in the blood.
The radionuclides technetium-99m, cobalt-57, gallium-67, gallium-68, indium-111 and indium-113m have shorter half lives or emit lower energy gamma rays than iodine-131 and would be preferred in complexes with rose bengal. However rose bengal does not complex satisfactorily with such radionuclides.
Loberg et al., U.S. Pat. No. 4,017,596 disclose that chelates of the radiometals technetium-99m, cobalt-57, gallium-67, gallium-68, indium-111 or indium-113m with a substituted iminodiacetic acid serve as useful radiopharmaceutical imaging agents for liver. The chelating agent is preferably of the formula ##STR1## wherein R may be alkyl of up to about 24 carbon atoms, preferably about 14 carbon atoms, alkenyl, aryl alkyl or cycloaliphatic groups, substituted with halogen, hydroxy, carboxy, nitro, amino, keto or heterocyclic groups, each of which may be substituted by ether or thio-ether linkages. Additional chelating agents disclosed are compounds wherein R is combined with each methylene group to form a heterocyclic ring.
However, the Loberg et al. patent does not disclose that any member of the broad class of substituted iminodiacetic acid chelates disclosed therein is sufficiently specific to the liver as to be excreted solely by the liver. In fact, Loberg et al. indicate that chelates within the general class disclosed are cleared through either the kidneys or the liver. A chelate which is excreted through both the kidneys and liver or is reabsorbed from the gastrointestinal tract would not fit the two compartment model. Instead such a chelate would follow a three or more compartment model, and semilog plots of the chelate's experimentally measured radiopharmaceutical activity in the liver versus time could not be analyzed and quantified to assess liver function as simply as can similar plots for a chelate following a two compartment model.